Petrushina Irina, Davtyan Hayk, Hovakimyan Armine, Davtyan Arpine, Passos Giselle F, Cribbs David H, Ghochikyan Anahit, Agadjanyan Michael G
Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92697, USA.
Department of Molecular Immunology, Institute for Molecular Medicine, Huntington Beach, CA 92647, USA.
Mol Ther. 2017 Jan 4;25(1):153-164. doi: 10.1016/j.ymthe.2016.10.002.
Previously, we reported that Alzheimer's disease (AD) epitope vaccines (EVs) composed of N-terminal β-amyloid (Aβ) B cell epitope fused with universal foreign T helper (Th) epitope(s) were immunogenic, potent, and safe in different amyloid precursor protein (APP) transgenic mice with early AD-like pathology. However, developing an effective therapeutic vaccine is much more challenging, especially when a self-antigen such as Aβ is a target. Here, we directly compare the efficacy of anti-Aβ antibodies in Tg2576 mice with low or high levels of AD-like pathology at the start of immunizations: 6-6.5 months for preventive vaccinations and 16-19 months for therapeutic vaccinations. EV in a preventive setting induced high levels of anti-Aβ antibodies, significantly reducing pathologic forms of Aβ in the brains of Tg2576 mice. When used therapeutically for immunesenescent Tg2576 mice, EV induced low levels of antibodies not sufficient for clearing of AD-like pathology. Separately, we demonstrated that EV was also not effective in 11-11.5-month-old Tg2576 mice with moderate AD-like pathology. However, we augmented the titers of anti-Aβ antibodies in transgenic (Tg) mice of the same age possessing the pre-existing memory Th cells and detected a significant decrease in diffuse and core plaques in cortical regions compared to control animals along with improved novel object recognition performance.
此前，我们报道过，由与通用外源T辅助（Th）表位融合的N端β淀粉样蛋白（Aβ）B细胞表位组成的阿尔茨海默病（AD）表位疫苗（EVs），在具有早期AD样病理的不同淀粉样前体蛋白（APP）转基因小鼠中具有免疫原性、效力强且安全。然而，开发一种有效的治疗性疫苗更具挑战性，尤其是当诸如Aβ这样的自身抗原作为靶点时。在此，我们直接比较了在免疫开始时具有低水平或高水平AD样病理的Tg2576小鼠中抗Aβ抗体的效力：预防性疫苗接种为6 - 6.5个月，治疗性疫苗接种为16 - 19个月。预防性接种时，EV诱导产生高水平的抗Aβ抗体，显著减少了Tg2576小鼠大脑中Aβ的病理形式。当用于免疫衰老的Tg2576小鼠进行治疗时，EV诱导产生的抗体水平较低，不足以清除AD样病理。另外，我们证明EV对具有中度AD样病理的11 - 11.5月龄Tg2576小鼠也无效。然而，我们提高了具有预先存在的记忆性Th细胞的同年龄转基因（Tg）小鼠中抗Aβ抗体的滴度，并且与对照动物相比，检测到皮质区域的弥漫性和核心斑块显著减少，同时新颖物体识别性能得到改善。
